Enzyme activity allosteric regulation

Two mechanisms that are commonly employed in altering enzyme activity are covalent modification and allosteric regulation. Covalent modification is an enzymatically catalyzed reaction that involves the reversible formation of a covalent bond between a small molecule and a specific amino acid side chain(s) on an enzyme that affects its activity. Allosteric regulation of an enzyme s activity involves noncovalent binding of a small molecule at a site other than the active site that alters the enzyme s activity. Unlike the limited examples of covalent modification that have been discovered (see Table 15-1), a wide variety of small molecules have been found to regulate the activity of particular enzymes allosterically. 

Nonprotein Biocatalysts Ribozymes (Figure 11.29, Figure 11.30) The Regulation of Enzyme Activity Allosteric Enzymes... 

Regulatory or allosteric enzymes like enzyme 1 are, in some instances, regulated by activation. That is, whereas some effector molecules such as F exert negative effects on enzyme activity, other effectors show stimulatory, or positive, influences on activity. 

Metabolic regulation is achieved via regulating enzyme activity in three prominent ways allosteric regulation, covalent modi-... 

The hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate (Eigure 23.7), like all phosphate ester hydrolyses, is a thermodynamically favorable (exergonic) reaction under standard-state conditions (AG° = —16.7 kj/mol). Under physiological conditions in the liver, the reaction is also exergonic (AG = —8.6 kJ/mol). Fructose-1,6-bisphosphatase is an allosterically regulated enzyme. Citrate stimulates bisphosphatase activity, hut fructose-2,6-bisphosphate is a potent allosteric inhibitor. / MP also inhibits the bisphosphatase the inhibition by / MP is enhanced by fructose-2,6-bisphosphate. 

The lack of structural similarity between a feedback inhibitor and the substrate for the enzyme whose activity it regulates suggests that these effectors are not isosteric with a substrate but allosteric ( occupy another space ). Jacques Monod therefore proposed the existence of allosteric sites that are physically distinct from the catalytic site. Allosteric enzymes thus are those whose activity at the active site may be modulated by the presence of effectors at an allosteric site. This hypothesis has been confirmed by many lines of evidence, including x-ray crystallography and site-directed mutagenesis, demonstrating the existence of spatially distinct active and allosteric sites on a variety of enzymes. 

Metabolic pathways are regulated by rapid mechanisms affecting the activity of existing enzymes, eg, allosteric and covalent modification (often in response to hormone action) and slow mechanisms affecting the synthesis of enzymes. 

Figure 11. Allosteric regulation A conformational change of the active site of an enzyme induced by reversible binding of an effector molecule (A). The model of Monod, Wyman, and Changeux (B) Cooperativity in the MWC is induced by a shift of the equilibrium between the T and R state upon binding of the receptor. Note that the sequential dissociation constants Kr and KR do not change. The T and R states of the enzyme differ in their catalytic properties for substrates. Both plots are adapted from Ref. 140. See color insert.

Phosphorylase was studied in depth. The enzyme from muscle was different from that catalyzing the same reaction in liver. Muscle phosphorylase but not that from liver, was activated by AMP, an early example of enzyme regulation by a ligand which was not a substrate. [Allosteric regulation was not postulated until the work of Jacob and... 

Allosteric regulators bind to the target enzyme in a non-covalent manner. An entirely different enzyme control mechanism is covalent modification. Here, the conformation of the enzyme protein, and thereby its activity, is changed by the... 

To provide a mechanism for the feedback inhibition of these enzymes, the allosteric model was put forward in 1963. It was proposed that the enzyme that regulates the flux through a pathway has two distinct binding sites, the active site and a separate site to which the regulator binds. This was termed the allosteric site. The word allosteric means different shape , which in the context of this mechanism means a different shape from the substrate. The theory further proposed that when the regnlator binds to the allosteric site, it canses a conformational change in... 

Figure 3.14 Diagram illustrating regulation of enzyme activity by an allosteric regulator. Note the representation of the conformational change.

It is possible for an enzyme to be regulated by several different external regulators that all bind at different allosteric sites on the enzyme. In this case, if the concentrations of all the regulators change in directions to change the activity of the enzyme in the same direction, the effect of all external regulators could be cumulative (Figure 3.29). 

Figure 3.29 Control of an enzyme activity by multiple allosteric regulators. The enzyme glycogen phosphorylase b in muscle is regulated by changes in the concentrations of AMP and inosine monophosphate (IMP) (which are activators) and ATP and glucose 6-phosphate (G6P), which are inhibitors.

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